This proposal focuses on how homeostatic proliferation of T cells influences their capacity to make an anti-viral response. Homeostatic proliferation is a mechanism through which mature naive T cells undergo cell division and apparent conversion to memory cells ("pseudo-memory" T cells) in response to T cell immunodeficiency. While this process is well studied in isolation, its impact on the generation and maintenance of memory cells which can respond to infectious agents has not been studied. Here we will examine how CD8 T cell responses to Vaccinia, a pox virus still used as the vaccine for Small Pox, is influenced by homeostatic proliferation. The anti-viral response of these pseudo-memory T cells will be compared to both naive T cells and true or "bona fide" memory T cells which we will generate by deliberate vaccination. The use of TCR transgenic T cells will allow us to compare T cell populations in these various differentiation states, yet maintain the identical TCR on each population. There are three Specific Aims. In Aim #1, we will determine whether TCR transgenic T cells which have undergone homeostatic proliferation (pseudo-memory T cells) respond similarly or differently from bona fide memory T ceils. This will involve measurement of T cell survival, maintenance, stimulation by viral infection and ability to contribute to viral clearance. In Aim #2, we will address whether the maintenance and/or reactivity of pseudo-memory T cells can be enhanced (or impaired) by vaccination. Finally, in Aim #3, we will reverse the experimental system and ask whether bona fide memory T cells are able to participate in homeostatic proliferation and whether these ceils maintain their functional properties.